The use of large language models (LLMs) to simulate human behavior has gained significant attention, particularly through personas that approximate individual characteristics. Persona-based simulations hold promise for transforming disciplines that rely on population-level feedback, including social science, economic analysis, marketing research, and business operations. Traditional methods to collect realistic persona data face significant challenges. They are prohibitively expensive and logistically challenging due to privacy constraints, and often fail to capture multi-dimensional attributes, particularly subjective qualities. Consequently, synthetic persona generation with LLMs offers a scalable, cost-effective alternative. However, current approaches rely on ad hoc and heuristic generation techniques that do not guarantee methodological rigor or simulation precision, resulting in systematic biases in downstream tasks. Through extensive large-scale experiments including presidential election forecasts and general opinion surveys of the U.S. population, we reveal that these biases can lead to significant deviations from real-world outcomes. Our findings underscore the need to develop a rigorous science of persona generation and outline the methodological innovations, organizational and institutional support, and empirical foundations required to enhance the reliability and scalability of LLM-driven persona simulations. To support further research and development in this area, we have open-sourced approximately one million generated personas, available for public access and analysis at https://huggingface.co/datasets/Tianyi-Lab/Personas.